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Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype

Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the function of motile cilia, resulting in chronic upper and lower respiratory disease, reduced fertility, and a high prevalence of situs abnormalities. The disease is genetically and phenotypically heterogeneous...

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Autores principales: Ostrowski, Lawrence E., Yin, Weining, Smith, Amanda J., Sears, Patrick R., Bustamante-Marin, Ximena M., Dang, Hong, Hildebrandt, Friedhelm, Daniels, Leigh Anne, Capps, Nicole A., Sullivan, Kelli M., Leigh, Margaret W., Zariwala, Maimoona A., Knowles, Michael R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835943/
https://www.ncbi.nlm.nih.gov/pubmed/35163670
http://dx.doi.org/10.3390/ijms23031753
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author Ostrowski, Lawrence E.
Yin, Weining
Smith, Amanda J.
Sears, Patrick R.
Bustamante-Marin, Ximena M.
Dang, Hong
Hildebrandt, Friedhelm
Daniels, Leigh Anne
Capps, Nicole A.
Sullivan, Kelli M.
Leigh, Margaret W.
Zariwala, Maimoona A.
Knowles, Michael R.
author_facet Ostrowski, Lawrence E.
Yin, Weining
Smith, Amanda J.
Sears, Patrick R.
Bustamante-Marin, Ximena M.
Dang, Hong
Hildebrandt, Friedhelm
Daniels, Leigh Anne
Capps, Nicole A.
Sullivan, Kelli M.
Leigh, Margaret W.
Zariwala, Maimoona A.
Knowles, Michael R.
author_sort Ostrowski, Lawrence E.
collection PubMed
description Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the function of motile cilia, resulting in chronic upper and lower respiratory disease, reduced fertility, and a high prevalence of situs abnormalities. The disease is genetically and phenotypically heterogeneous, with causative mutations in > 50 genes identified, and clinical phenotypes ranging from mild to severe. Absence of ODAD1 (CCDC114), a component of the outer dynein arm docking complex, results in a failure to assemble outer dynein arms (ODAs), mostly immotile cilia, and a typical PCD phenotype. We identified a female (now 34 years old) with an unusually mild clinical phenotype who has a homozygous non-canonical splice mutation (c.1502+5G>A) in ODAD1. To investigate the mechanism for the unusual phenotype, we performed molecular and functional studies of cultured nasal epithelial cells. We demonstrate that this splice mutation results in the expression of a truncated protein that is attached to the axoneme, indicating that the mutant protein retains partial function. This allows for the assembly of some ODAs and a significant level of ciliary activity that may result in the atypically mild clinical phenotype. The results also suggest that partial restoration of ciliary function by therapeutic agents could lead to significant improvement of disease symptoms.
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spelling pubmed-88359432022-02-12 Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype Ostrowski, Lawrence E. Yin, Weining Smith, Amanda J. Sears, Patrick R. Bustamante-Marin, Ximena M. Dang, Hong Hildebrandt, Friedhelm Daniels, Leigh Anne Capps, Nicole A. Sullivan, Kelli M. Leigh, Margaret W. Zariwala, Maimoona A. Knowles, Michael R. Int J Mol Sci Article Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the function of motile cilia, resulting in chronic upper and lower respiratory disease, reduced fertility, and a high prevalence of situs abnormalities. The disease is genetically and phenotypically heterogeneous, with causative mutations in > 50 genes identified, and clinical phenotypes ranging from mild to severe. Absence of ODAD1 (CCDC114), a component of the outer dynein arm docking complex, results in a failure to assemble outer dynein arms (ODAs), mostly immotile cilia, and a typical PCD phenotype. We identified a female (now 34 years old) with an unusually mild clinical phenotype who has a homozygous non-canonical splice mutation (c.1502+5G>A) in ODAD1. To investigate the mechanism for the unusual phenotype, we performed molecular and functional studies of cultured nasal epithelial cells. We demonstrate that this splice mutation results in the expression of a truncated protein that is attached to the axoneme, indicating that the mutant protein retains partial function. This allows for the assembly of some ODAs and a significant level of ciliary activity that may result in the atypically mild clinical phenotype. The results also suggest that partial restoration of ciliary function by therapeutic agents could lead to significant improvement of disease symptoms. MDPI 2022-02-03 /pmc/articles/PMC8835943/ /pubmed/35163670 http://dx.doi.org/10.3390/ijms23031753 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ostrowski, Lawrence E.
Yin, Weining
Smith, Amanda J.
Sears, Patrick R.
Bustamante-Marin, Ximena M.
Dang, Hong
Hildebrandt, Friedhelm
Daniels, Leigh Anne
Capps, Nicole A.
Sullivan, Kelli M.
Leigh, Margaret W.
Zariwala, Maimoona A.
Knowles, Michael R.
Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype
title Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype
title_full Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype
title_fullStr Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype
title_full_unstemmed Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype
title_short Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype
title_sort expression of a truncated form of odad1 associated with an unusually mild primary ciliary dyskinesia phenotype
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835943/
https://www.ncbi.nlm.nih.gov/pubmed/35163670
http://dx.doi.org/10.3390/ijms23031753
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